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Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies

  • PHASE I STUDIES
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Summary

Introduction Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤30% of patients. Methods Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, performance status of 0–2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1. Results Twelve patients were enrolled: median age 65 years (range 49–74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 at DL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n = 1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, 525 East 68th Street, 3rd floor, New York, NY, 10065, USA

    Bryan J. Schneider

  2. University of Michigan, Ann Arbor, MI, USA

    Gregory P. Kalemkerian, David C. Smith & Maha Hussain

  3. Duke University, 10 Bryan Searle Drive, 477 Seeley G. Mudd Building, Durham, NC, 27710, USA

    Deborah Bradley

  4. University of Pittsburgh Cancer Institute, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA, 15213-1862, USA

    Merrill J. Egorin

  5. Biostatistics Core Facility, University of Michigan Cancer Center, Ann Arbor, MI, USA

    Stephanie Daignault & Rodney Dunn

  6. C350 Med Inn, 1500 E. Medical Center Drive, Box 5848, Ann Arbor, MI, 48109, USA

    Gregory P. Kalemkerian

  7. 7302 CCGC, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-0946, USA

    David C. Smith

  8. UMCCC Biostatistics Unit, 300 N. Ingalls, 8D09, Ann Arbor, MI, 48109-0473, USA

    Stephanie Daignault

  9. Department of Urology, UMCCC Biostatistics Unit, 300 N. Ingalls, 8D15, Ann Arbor, MI, 48109-0473, USA

    Rodney Dunn

  10. 1500 E. Medical Center Drive, 7314 CCGC, Ann Arbor, MI, 48109-0946, USA

    Maha Hussain

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Supported in part by a grant from Merck & Co., Inc.

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Schneider, B.J., Kalemkerian, G.P., Bradley, D. et al. Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies. Invest New Drugs 30, 249–257 (2012). https://doi.org/10.1007/s10637-010-9503-6

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